Development and validation of a risk prediction model and prediction tools for post-thrombotic syndrome in patients with lower limb deep vein thrombosis.

PURPOSE: Our research aims to compare the predictive performance of decision tree algorithms (DT) and logistic regression analysis (LR) in constructing models, and develop a Post-Thrombotic Syndrome (PTS) risk stratification tool. METHODS: We retrospectively collected and analyzed relevant case information of 618 patients diagnosed with DVT from January 2012 to December 2021 in three different tertiary hospitals in Jiangxi Province as the modeling group. Additionally, we used the case information of 212 patients diagnosed with DVT from January 2022 to January 2023 in two tertiary hospitals in Hubei Province and Guangdong Province as the validation group. We extracted electronic medical record information including general patient data, medical history, laboratory test indicators, and treatment data for analysis. We established DT and LR models and compared their predictive performance using receiver operating characteristic (ROC) curves and confusion matrices. Internal and external validations were conducted. Additionally, we utilized LR to generate nomogram charts, calibration curves, and decision curves analysis (DCA) to assess its predictive accuracy. RESULTS: Both DT and LR models indicate that Year, Residence, Cancer, Varicose Vein Operation History, DM, and Chronic VTE are risk factors for PTS occurrence. In internal validation, DT outperforms LR (0.962 vs 0.925, z = 3.379, P < 0.001). However, in external validation, there is no significant difference in the area under the ROC curve between the two models (0.963 vs 0.949, z = 0.412, P = 0.680). The validation results of calibration curves and DCA demonstrate that LR exhibits good predictive accuracy and clinical effectiveness. A web-based calculator software of nomogram (https://sunxiaoxuan.shinyapps.io/dynnomapp/) was utilized to visualize the logistic regression model. CONCLUSIONS: The combination of decision tree and logistic regression models, along with the web-based calculator software of nomogram, can assist healthcare professionals in accurately assessing the risk of PTS occurrence in individual patients with lower limb DVT.

A novel PKHD1 splicing variant identified in a fetus with autosomal recessive polycystic kidney disease.

Objective: Variants of the polycystic kidney and hepatic disease 1 (PKHD1) gene are associated with autosomal recessive polycystic kidney disease (ARPKD). This study aimed to identify the genetic causes in a Chinese pedigree with ARPKD and design a minigene construct of the PKHD1 gene to investigate the impact of its variants on splicing. Methods: Umbilical cord samples from the proband and peripheral blood samples from his parents were collected, and genomic DNA was extracted for whole-exome sequencing (WES). Bioinformatic analysis was used to identify potential genetic causes, and Sanger sequencing confirmed the existence of variants within the pedigree. A minigene assay was performed to validate the effects of an intronic variant on mRNA splicing. Results: Two variants, c.9455del (p.N3152Tfs*10) and c.2408-13C>G, were identified in the PKHD1 gene (NM_138694.4) by WES; the latter has not been previously reported. In silico analysis predicted that this intronic variant is potentially pathogenic. Bioinformatic splice prediction tools revealed that the variant is likely to strongly impact splice site function. An in vitro minigene assay revealed that c.2408-13C>G can cause aberrant splicing, resulting in the retention of 12 bp of intron 23. Conclusion: A novel pathogenic variant of PKHD1, c.2408-13C>G, was found in a fetus with ARPKD, which enriches the variant spectrum of the PKHD1 gene and provides a basis for genetic counseling and the diagnosis of ARPKD. Minigenes are optimal to determine whether intron variants can cause aberrant splicing.

Soluble CD146, a cerebrospinal fluid marker for neuroinflammation, promotes blood-brain barrier dysfunction.

The blood-brain barrier (BBB) dysfunction is an initial event of various neuroinflammatory diseases. However, the absence of reliable markers and mechanisms for BBB damage greatly limits the diagnosis and treatment of neuroinflammatory diseases. Soluble CD146 (sCD146) is mainly derived from vascular endothelial cells (ECs) and highly elevated in inflammatory settings. Based on a small cohort, our previous study showed that sCD146 is elevated in the cerebrospinal fluid (CSF) of multiple sclerosis (MS), which is accompanied with BBB damage. Nevertheless, whether sCD146 monitors and regulates the BBB dysfunction remains unknown. Methods: Coupled serum and CSF samples from patients with or without neuroinflammatory diseases were collected via multicenter collaborations. sCD146 was measured by sandwich ELISA using anti-CD146 antibodies AA1 and AA98, both of which were generated in our laboratory. The correlations between sCD146 and other clinical parameters or inflammatory factors were analyzed by Spearman's correlation coefficient analysis. The role of sCD146 on BBB function was examined in an in vitro BBB model. Results: Between July 20, 2011, and February 31, 2017, we collected coupled serum and CSF samples from 823 patients, of which 562 (68.3%) had neuroinflammatory diseases, 44 (5.3%) had remitting MS, and 217 (26.4%) had non-inflammatory neurological diseases (NIND). We found that sCD146 in CSF, but not in serum, is abnormally elevated in neuroinflammatory diseases (37.3 ± 13.3 ng/mL) compared with NIND (4.7 ± 2.9 ng/mL) and remitting MS (4.6 ± 3.5 ng/mL). Abnormally elevated CSF sCD146 is significantly correlated with the hyperpermeability-related clinical parameters of BBB and neuroinflammation-related factors. Moreover, CSF sCD146 shows higher sensitivity and specificity for evaluating BBB damage. Using an in vitro BBB model, we found that sCD146 impairs BBB function by promoting BBB permeability via an association with integrin αvß1. Blocking integrin αvß1 significantly attenuates sCD146-induced hyperpermeability of the BBB. Conclusion: Our study provides convincing evidence that CSF sCD146 is a sensitive marker of BBB damage and neuroinflammation. Furthermore, sCD146 is actively involved in BBB dysfunction.

Differential Diagnosis of Parkinson Disease, Essential Tremor, and Enhanced Physiological Tremor with the Tremor Analysis of EMG.

We investigate the differential diagnostic value of tremor analysis of EMG on Parkinson's disease (PD), essential tremor (ET), and enhanced physiological tremor (EPT). Clinical data from 25 patients with PD, 20 patients with ET, and 20 patients with EPT were collected. The tremor frequency and muscle contraction pattern of the resting, posture, and 500 g and 1000 g overload were recorded. The frequency of PD tremor was 4-6 Hz, and the frequency of ET was also in this range; the frequency of EPT is 6-12 hz having some overlap with PD. The muscle contraction patterns of the ET and EPT group were mainly synchronous contraction, and the muscle contraction mode of the PD group was mainly alternating contraction. Having tremor latency from rest to postural position and having changes in tremor amplitude after mental concentration in PD might distinguish ET. Tremor analysis of EMG was able to distinguish PD from ET and EPT by varying the tremor frequency and muscle contraction pattern. It can also differentiate between PD and ET by the latency and concentration effect and ET and EPT by weight load effect.

Macrophagic CD146 promotes foam cell formation and retention during atherosclerosis.

The persistence of cholesterol-engorged macrophages (foam cells) in the artery wall fuels the development of atherosclerosis. However, the mechanism that regulates the formation of macrophage foam cells and impedes their emigration out of inflamed plaques is still elusive. Here, we report that adhesion receptor CD146 controls the formation of macrophage foam cells and their retention within the plaque during atherosclerosis exacerbation. CD146 is expressed on the macrophages in human and mouse atheroma and can be upregulated by oxidized low-density lipoprotein (oxLDL). CD146 triggers macrophage activation by driving the internalization of scavenger receptor CD36 during lipid uptake. In response to oxLDL, macrophages show reduced migratory capacity toward chemokines CCL19 and CCL21; this capacity can be restored by blocking CD146. Genetic deletion of macrophagic CD146 or targeting of CD146 with an antibody result in much less complex plaques in high-fat diet-fed ApoE-/- mice by causing lipid-loaded macrophages to leave plaques. Collectively, our findings identify CD146 as a novel retention signal that traps macrophages within the artery wall, and a promising therapeutic target in atherosclerosis treatment.

[A correlation study of adhesion molecule CD146 and the vulnerability of carotid atherosclerotic plaque].

OBJECTIVE: To investigate the correlation between the expression of adhesion molecule CD146 and the vulnerability of carotid atherosclerotic plaque. METHODS: The plaque samples were collected from 40 patients who underwent the carotid endarterectomy and were divided into the stable plaque group and the instable plaque group by ultrasound imaging. Five carotid artery samples were taken from the healthy donors as the control. Immunohistochemistry was applied to test the CD146 expression in all samples. RESULTS: Higher expression of CD146 was observed in the atherosclerotic plaques than in the healthy control. Moreover, statistical difference was found in the expression of CD146 in the plaques between the instable plaque group and the stable plaque group (0.31 ± 0.19 vs 0.17 ± 0.07, P < 0.05). The expression of CD146 was positively correlated with the necrotic area (r = 0.471 8, P = 0.019 9) and the matrix metalloproteinase (MMP)-9 expression in the plaques (r = 0.535 6, P = 0.000 9). CONCLUSION: The CD146 expression is correlated with the vulnerability of carotid atherosclerotic plaque.

[The influence of oil heat treatment on wood decay resistance by Fourier infrared spectrum analysis].

Wood preservative treatment can improve defects of plantation wood such as easy to corrupt and moth eaten. Among them heat-treatment is not only environmental and no pollution, also can improve the corrosion resistance and dimension stability of wood. In this test Poplar and Mongolian Seoteh Pine was treated by soybean oil as heat-conducting medium, and the heat treatment wood was studied for indoor decay resistance; wood chemical components before and after treatment, the effect of heat treatment on wood decay resistance performance and main mechanism of action were analysed by Fourier infrared spectrometric. Results showed that the mass loss rate of poplar fell from 19.37% to 5% and Mongolian Seoteh Pine's fell from 8.23% to 3.15%, so oil heat treatment can effectively improve the decay resistance. Infrared spectrum analysis shows that the heat treatment made wood's hydrophilic groups such as hydroxyl groups in largely reduced, absorbing capacity decreased and the moisture of wood rotting fungi necessary was reduced; during the heat treatment wood chemical components such as cellulose, hemicellu lose were degraded, and the nutrient source of wood rotting fungi growth necessary was reduced. Wood decay fungi can grow in the wood to discredit wood is because of that wood can provide better living conditions for wood decay fungi, such as nutrients, water, oxygen, and so on. The cellulose and hemicellulose in wood is the main nutrition source of wood decay fungi. So the oil heat-treatment can reduce the cellulose, hemicellulose nutrition source of wood decay fungi so as to improve the decay resistance of wood.

Adhesion molecule CD146 and its soluble form correlate well with carotid atherosclerosis and plaque instability.

AIMS: Intraplaque neovascularization and foam cell infiltration contribute to the development of unstable plaque, leading to thromboembolism and stroke. Cell adhesion molecules (CAMs) have been reported to be involved in the progression of atherosclerosis and plaque vulnerability. The aim of this study was to assess the association of adhesion molecule CD146 with carotid plaque instability. METHODS: We collected forty atherosclerotic plaques from 40 patients undergoing carotid endarterectomy. The clinical information of each patient was obtained, and the plaque morphology and characteristics were examined by the ultrasound. The CD146 expressions of the plaques were graded by using semiquantitative scales. The serum level of soluble form of CD146 was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: CD146 expression was mainly on the intraplaque blood vessels and infiltrated macrophages. The CD146 expression was strongly correlated with the matrix metalloproteinase-9(MMP-9)expressions (P < 0.001) in the plaques. Soluble CD146 (sCD146) was also elevated in patients with atherosclerotic plaques. There was significant correlation between the increased CD146 expression and sCD146 level (P = 0.0057). sCD146 correlated well with serum MMP-9 (P < 0.0044), IL-6 (P = 0.0044) and high sensitivity C-reactive protein (hsCRP) (P = 0.005). CONCLUSIONS: Adhesion molecules CD146 and its soluble form strongly correlated with the development of inflammation of atherosclerosis and plaque instability. CD146 may be a promising biomarker for monitoring the development and instability of atherosclerotic plaque in patients with carotid diseases.

[Association between serum soluble CD146 level and plaque vulnerability in carotid atherosclerosis].

OBJECTIVE: To explore the relationship between circulating level of soluble CD146 (sCD146) and plaque vulnerability or inflammatory factors in patients with carotid atherosclerosis (CAS). METHODS: Forty CAS patients with carotid stenosis ( ≥ 70%) were enrolled and divided into 2 groups of stable and unstable plaque by ultrasonic imaging. And another 40 healthy subjects were enrolled for control group. Double-antibody sandwich enzyme-linked immunosorbent assay (ELISA) was employed to measure the serum levels of sCD146 and matrix metalloproteinase-9 (MMP-9), analyze the correlation of sCD146 with MMP-9 and high sensitivity CRP (hs-CRP), and evaluate whether sCD146 correlates with plaque vulnerability. RESULTS: Soluble CD146 level was elevated in CAS patients versus healthy donors [(212 ± 43) vs (173 ± 36) ng/ml, P < 0.001]. And sCD146 level significantly increased in CAS patients with unstable plaques than those with stable plaque [(218 ± 28) vs (176 ± 25) ng/ml, P < 0.001]. And sCD146 was correlated with high-sensitivity C-reactive protein (hsCRP, r = 0.370 9, P = 0.018 5), a well-known marker for CAS inflammation. Also it was an independent risk factor for plaque vulnerability (OR = 1.16, 95%CI:1.020-1.310, P = 0.019 2). And its level was not correlated with the risk factors of CAS, such as age, homocysteine, triglyceride, total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) or high density lipoprotein-cholesterol (HDL-C) (P > 0.05). But there was a good correlation with the serum level of MMP-9 in CAS patients (r = 0.677 2, P < 0.001). CONCLUSION: The concentration of soluble CD146 is positively correlated with hsCRP and MMP-9 in CAS patients. And inflammation and neovascularization may interact with each other during atherosclerotic process. The serum level of sCD146 is correlated independently with plaque vulnerability.

Targeting endothelial CD146 attenuates neuroinflammation by limiting lymphocyte extravasation to the CNS.

The ability to selectively block the entry of leukocytes into the central nervous system (CNS) without compromising the immune system is an attractive therapeutic approach for treating multiple sclerosis (MS). Using endothelial CD146-deficienct mice as a MS model, we found that endothelial CD146 plays an active role in the CNS-directed extravasation of encephalitogenic T cells, including CD146(+) TH1 and TH17 lymphocytes. Moreover, treating both active and passive MS models with the anti-CD146 antibody AA98 significantly decreased the infiltrated lymphocytes in the CNS and decreased neuroinflammation. Interestingly, the ability of AA98 to inhibit the migration of CD146(+) lymphocytes was dependent on targeting endothelial CD146, but not lymphocytic CD146. These results suggest a key molecular target located on the blood-brain barrier endothelium that mediates the extravasation of inflammatory cells into the CNS. In addition, our data suggest that the AA98 is a promising candidate for treating MS and other CNS autoimmune diseases.

[Association between both triglyceride level, newly identified carotid plaque and middle-aged and elderly population, Beijing].

OBJECTIVE: To evaluate the association between triglyceride (TG) level and newly identified 5-year carotid plaque and to explore the prediction value of TG level on the newly-identified carotid plaque with risk factors of traditional atherosclerosis. METHODS: A cohort study was adopted. The baseline survey including CVD risk factors and B-mode ultrasound of carotid artery was performed in 2002, and the second follow-up examination was performed in 2007. We evaluated 1949 participants with lipid measurements and B-mode ultrasound of carotid arteries in the two surveys (with mean age as 57.9±8.1 years and 39.2% were men). The baseline TG levels were divided into four groups: group 1 (TG<1.13 mmol/L), group 2 (TG=1.13-1.69 mmol/L), group 3 (TG=1.70-2.25 mmol/L) and group 4 (TG≥2.26 mmol/L). Newly identified carotid plaque was regarded as the indicator of progression of carotid atherosclerosis. New relationship between fasting TG levels and newly identified carotid plaque was analysed. RESULTS: Compared to newly identified carotid plaque which including different TG level groups, the incidence of newly artery plaque had significantly increased along with the increase of baseline triglyceride level (30.8%, 38.8%, 41.9% and 44.2% respectively, with χ2=21.22, P<0.01). Compared to individuals (TG<1.13 mmol/L), TG seemed a risk factor of plaque progression (P<0.01). After adjusted for age, sex, dyslipidemia and other risk factors, high TG group (TG≥2.26 mmol/L) appeared a significant independent predictor of newly identified carotid plaque (OR=1.37, 95%CI: 1.00-1.86). When further stratifying the traditional atherosclerosis risk factors, we found that high TG group with smoking or hypertension was an independent factor of atherosclerosis progression. CONCLUSION: With the increase of triglyceride levels, the rate of newly identified carotid plaque also increased. After adjusting age, sex, dyslipidemia and other risk factors, serum fasting TG≥2.26 mmol/L appeared to be an independent predictor of newly developed carotid plaque.

Mutations in mitochondrially encoded complex I enzyme as the second common cause in a cohort of Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes.

The mutation pattern of mitochondrial DNA (mtDNA) in mainland Chinese patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) has been rarely reported, though previous data suggested that the mutation pattern of MELAS could be different among geographically localized populations. We presented the results of comprehensive mtDNA mutation analysis in 92 unrelated Chinese patients with MELAS (85 with classic MELAS and 7 with MELAS/Leigh syndrome (LS) overlap syndrome). The mtDNA A3243G mutation was the most common causal genotype in this patient group (79/92 and 85.9%). The second common gene mutation was G13513A (7/92 and 7.6%). Additionally, we identified T10191C (p.S45P) in ND3, A11470C (p. K237N) in ND4, T13046C (p.M237T) in ND5 and a large-scale deletion (13025-13033:14417-14425) involving partial ND5 and ND6 subunits of complex I in one patient each. Among them, A11470C, T13046C and the single deletion were novel mutations. In summary, patients with mutations affecting mitochondrially encoded complex I (MTND) reached 12.0% (11/92) in this group. It is noteworthy that all seven patients with MELAS/LS overlap syndrome were associated with MTND mutations. Our data emphasize the important role of MTND mutations in the pathogenicity of MELAS, especially MELAS/LS overlap syndrome.

Characteristics and risk factors of cerebrovascular accidents after percutaneous coronary interventions in patients with history of stroke.

BACKGROUND: Percutaneous coronary intervention (PCI) is a well-established method for managing coronary diseases. However, the increasing use of PCI has led to an increased incidence of acute cerebrovascular accidents (CVA) related to PCI. In this study, we investigated the characteristics and risk factors of CVA after PCI in patients with known stroke history. METHODS: Between January 1, 2005 and March 1, 2009, 621 patients with a history of stroke underwent a total of 665 PCI procedures and were included in this retrospective study. Demographic and clinical characteristics, previous medications, procedures, neurologic deficits, location of lesion and in-hospital clinical outcomes of patients who developed a CVA after the cardiac catheterization laboratory visit and before discharge were reviewed. RESULTS: Acute CVA was diagnosed in 53 (8.5%) patients during the operation or the perioperative period. Seventeen patients suffered from transient ischemic attack, thirty-four patients suffered from cerebral infarction and two patients suffered from cerebral hemorrhage. The risk factors for CVA after PCI in stroke patients were: admission with an acute coronary syndrome, use of an intra-aortic balloon pump, urgent or emergency procedures, diabetes mellitus, and poor left ventricular systolic function, arterial fibrillation, previous myocardial infarction, dyslipidemia, tobacco use, and no/irregular use of anti-platelet medications. CONCLUSIONS: The incidence of CVA during and after PCI in patients with history of stroke is much higher than that in patients without history of stroke. Patients with atrial fibrillation, previous myocardial infarction, diabetes mellitus, dyslipidemia, tobacco use, and no or irregular use of anti-platelet medications were at higher risk for recurrent stroke. This study showed a strong association between acute coronary syndromes and in-hospital stroke after PCI.

Cerebrotendinous xanthomatosis with a compound heterozygote mutation and severe polyneuropathy.

Cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessively inherited lipid storage disorder with multiple system involvement and has been reported worldwide. Here we report a Chinese family with CTX and present the pathological findings within peripheral nerves and CYP27A1 gene mutation analysis. We also review the published literature to discuss the clinical presentation and classification of neuropathy in this disease.